Results of Two Phase I Clinical Trials of MVA-BN®-HER2 in HER-2 Overexpressing Metastatic Breast Cancer Patients.

Background:HER-2 targeted vaccine approaches appear promising for the treatment of breast cancer. HER-2 is an oncogenic growth factor receptor, is immunogenic, is expressed in stem cell subset of many breast cancers, and is overexpressed in 20–30% of human breast cancers. MVA-BN®-HER2 is a candidate immunotherapy product which utilizes a poxviral vector that encodes a modified form of the HER-2 protein. The MVA-BN® vector is a highly attenuated vaccinia virus, non-replicating in humans, which is an immunogenic vaccine vehicle. The vector induces minimal neutralizing antibodies and is capable of multiple immunizations. Preclinical data with mouse models demonstrates that immunization with MVA-BN®-HER2 can break tolerance in a transgenic model and has anti tumor activity against HER-2 expressing tumors.Methods: MVA-BN®-HER2 was evaluated in two fixed-dose, single arm studies. The first study, based in Poland and Serbia (7 sites), evaluated 21 patients (pts) either following first or second-line chemotherapy (10 pts), or in a separate cohort, in combination with single agent taxane chemotherapy (11 pts). The second study, based in the US (2 sites), evaluated 9 patients following first- or second-line chemotherapy. Patients were vaccinated with 1x108 TCID50 subcutaneously, 3 times, at 3 week intervals. Eligible patients had metastatic disease, with stable disease or better after chemotherapy. Patients with brain metastasis were excluded. The endpoints were safety and immunogenicity.Results: Twenty-eight patients received all three vaccinations. Vaccinations were well tolerated with typically only local injection site reactions as side effects. No dose-limiting toxicities were recorded, and no patient discontinued due to an adverse event. Two patients discontinued after 2 vaccinations due to disease progression. Two patients had asymptomatic declines in LV ejection fraction, possibly but unlikely related to vaccination. Both were heavily pretreated with anthracyclines and Herceptin, and one was on concurrent Herceptin. Both resolved on follow-up ECHO within 1 and 2 months. In the group where vaccine was combined with chemotherapy, one complete response and one partial response were observed. With 6 months of follow-up, after completion of treatment, 15 out of 28 patients have not progressed. Immune evaluation of samples from patients treated with MVA BN®-HER2 revealed that treatment was able to break tolerance against HER-2 in a metastatic setting, inducing either a humoral and/or T-cell response in greater than 66% of the patients. Specifically, HER-2 specific antibodies were detected in more than 50% of patients tested. And although modest (50-100 spots per 106 PBMC), T-cell responses were boosted post treatment (with at least one HER-2 reagent peptide pools or recombinant protein) in five out of eight patients upon stimulation.Conclusions: These preliminary data show that MVA-BN®-based, HER2-directed vaccination is a biologically active treatment for patients with HER-2- positive breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5089.